The Uncomfortable Truth: Open Thoracotomy versus Minimally Invasive Surgery in Lung Cancer: A Systematic Review and Meta-Analysis

Simple Summary Surgery is the preferred treatment of choice for early-stage lung cancer, but historically, it required large incisions (open surgery) for access and removal of the tumor. Latest guidelines recommend minimally invasive surgery (MIS) as a preferred option for lung cancer due to better clinical outcomes. However, there is insufficient RCT (randomized clinical trial) evidence to establish the superiority of MIS over open surgery. This study revealed selection bias and problems related to surgical approach, with no significant difference in major postoperative complications between thoracotomy and MIS. Therefore, it is reasonable to allow experienced surgeons to choose the appropriate surgical approach for each patient. Abstract For decades, lung surgery in thoracic cancer has evolved in two ways: saving more parenchyma and being minimally invasive. Saving parenchyma is a fundamental principle of surgery. However, minimally invasive surgery (MIS) is a matter of approach, so it has to do with advances in surgical techniques and tools. For example, MIS has become possible with the introduction of VATS (video-assisted thoracic surgery), and the development of tools has extended the indication of MIS. Especially, RATS (robot-assisted thoracic surgery) improved the quality of life for patients and the ergonomics of doctors. However, the dichotomous idea that the MIS is new and right but the open thoracotomy is old and useless may be inappropriate. In fact, MIS is exactly the same as a classic thoracotomy in that it removes the mass/parenchyma containing cancer and mediastinal lymph nodes. Therefore, in this study, we compare randomized-controlled trials about open thoracotomy and MIS to find out which surgical method is more helpful.


Introduction
The development of thoracic oncologic surgery has progressed from more to less invasive techniques [1]. For example, in the case of lung cancer, the standard extent of removal has shifted from pneumonectomy or bilobectomy to lobectomy or segmentectomy [2,3]. As for the approach or incisions, they were from full thoracotomy, anterolateral, or posterolateral thoracotomy to video-assisted thoracic surgery (VATS) or robot-assisted thoracic surgery (RATS) [4]. Although it may not necessarily be a superior procedure from an oncological standpoint, when a long-lasting scar is replaced by a few small holes and the number of holes decreases further over time, such a procedure is referred to as a progression in surgical techniques [5,6]. However, it is important to analysis. We compared preoperative demographics, tumor size, early mortality, postoperative complications such as bleeding, prolonged air leakage, respiratory fai and arrhythmia. Two authors (WW and JIS) extracted data from article texts, tables ures, and supplementary materials. They independently reviewed and evaluated quality of each study, and any discrepancies between them were resolved by a thoro discussion with two other authors (DK and SL). This study was not registered in PR PERO, and the PRISMA checklist was applied to evaluate this article ( Figure 1).

Statistical Analysis
Tumor size, patient age, operating time, and hospital stays were compared standardized mean difference. Postoperative complications after thoracotomy or V were compared using the RR and 95% confidence interval (CI). I2 statistics were use evaluate heterogeneity, and I2 > 50% was considered to represent significant heterog ity. Due to the low heterogeneity among studies, fixed effect models were use demonstrate each comparison between VATS and thoracotomy. Statistical signific was defined as a two-sided p-value < 0.05. Statistical analyses were performed usi version 4.1.0 (R Foundation for Statistical Computing, Vienna, Austria) and Rev Manager (RevMan) software version 5.2.3 (The Nordic Cochrane Centre, Copenha Denmark).

Statistical Analysis
Tumor size, patient age, operating time, and hospital stays were compared by standardized mean difference. Postoperative complications after thoracotomy or VATS were compared using the RR and 95% confidence interval (CI). I 2 statistics were used to evaluate heterogeneity, and I 2 > 50% was considered to represent significant heterogeneity. Due to the low heterogeneity among studies, fixed effect models were used to demonstrate each comparison between VATS and thoracotomy. Statistical significance was defined as a two-sided p-value < 0.05. Statistical analyses were performed using R version 4.1.0 (R Foundation for Statistical Computing, Vienna, Austria) and Review Manager (RevMan) software version 5.2.3 (The Nordic Cochrane Centre, Copenhagen, Denmark).

GRADE Approach
Version 2 of the Cochrane risk of bias tool (ROB 2) for randomized studies was used for the six RCTs included in this study. Two surgical experts (S.L. and D.K.) and two specialists (J.I.S. and W.W.) with systematic reviews independently evaluated the risk of biases. Then, we used the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) approach to evaluate the certainty of evidence based on RCTs.

Collective Review of the Guidelines
To collect opinions on minimally invasive surgery (MIS) for lung cancers, considering awareness and timing of presentation, the following four guidelines were selected: ACCP 2013, ESMO 2017, NICE 2019, and NCCN 2023 in Table 1. All these guidelines present separate recommendations for small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). Although there are some differences in the indications for surgery, all the guidelines generally aim for stage I-IIIa lung cancer. There was no disagreement on the indication for surgery according to the staging, as stages I-II were included, but there were differences in the recommendations for stage IIIa. The extent of surgery was not disputed, with lobectomy being the standard operation; however, recent guidelines have recommended the need for anatomic segmentectomy in some early stages with groundglass opacity [28,29]. According to the guideline, sampling of mediastinal lymph nodes is sufficient rather than mediastinal lymph node dissection [28]. Opinions on video-assisted thoracic surgery (VATS), a type of MIS, varied according to the guidelines. ACCP 2013 preferred MIS over thoracotomy for anatomic pulmonary resection in stage I patients and suggested it in experienced centers [31]. However, the 2017 ESMO guidelines stated that either open thoracotomy or VATS could be used as appropriate to the expertise of the surgeon, although they recommended VATS as the appropriate approach for stage I [29]. Both guidelines, however, marked the level of evidence as 2C or V, C, indicating insufficient evidence and a lack of strong recommendations. According to the 2019 NICE guideline, both MIS and thoracotomy could be used for lung cancer surgery, but the 2023 NCCN guideline emphasized that MIS (VATS or RATS) should be strongly considered if the principles of surgery are applied, without specifying the stage [28,30]. In addition, it described excellent early results in terms of pain, hospitalization period, daily recovery, and complications in high-volume centers. In summary, early guidelines in the early 2010s allowed a choice between MIS and thoracotomy, limited to early-stage lung cancer, but recent guidelines recommend MIS, including VATS, for general lung cancer surgery without limitations in staging. However, considering various limitations, it is understandable what the guidelines aim to recommend. Nevertheless, it is questionable whether the evidence is clear.

Randomized Controlled Trials (RCTs) Comparing Open vs. VATS
Seven randomized controlled trials were included in this study, which compared open lobectomy (whether through posterolateral or anterior thoracotomy) versus VATS lobectomy. The inclusion and exclusion criteria used to allocate patients were reviewed. The clinical outcomes of each study were analyzed using meta-analysis methods. three cases had to be converted to thoracotomies, but they were excluded from the final analysis. From the perspective of intention to treat, the exclusion of these cases from the VATS group may have introduced bias in the clinical outcome assessment. On the other hand, some patients in the open group had such difficult surgeries (i.e., with a high possibility of poor clinical outcomes) that bronchial tears occurred during the dissection process and more than 500 mL of blood loss was observed, making it difficult to ensure that both groups had equivalent surgical difficulties. Furthermore, patients with stage II or higher were 36% in open and 20% in VATS.
Surgery: open (muscle sparing posterolateral thoracotomy) vs. VATS (no rib spreading but including 6-8 cm thoracotomy) Limitations: unequal assignment of patients with different surgical difficulties and disease stages.
In  [14]. Although the study referred to another paper for information on randomization, it was not specifically mentioned how randomization was performed, except that it involved peripheral bronchogenic carcinoma [1]. Both groups included patients with benign diseases (n = 4 in VATS and n = 1 in open) and were not equally allocated in terms of higher stage (stage III was none in VATS but n = 1 in open) and cell type (over six cell types were mixed). Interestingly, the VATS group included four patients with benign masses as well as patients with carcinoid, renal metastasis, melanoma metastasis, and high-grade sarcoma, for whom the surgical procedure performed may differ from that in general lung cancer patients, but there was no specific description of whether the surgeries performed on these patients were the same as those in general lung cancer patients.
Surgery: open (posterolateral thoracotomy) vs. VATS (4-5 cm incision with three ports) Limitations: patients with metastatic and benign tumors, who are expected to have different principles of surgery, are included in the VATS group, and the allocation of disease stage is not equal.
In Limitations: There were 86 patients who were not asked about their willingness to participate in the study (which represents 29% of the total patients if they had all participated), and 411 patients were deemed ineligible for the study, but the specific criteria for this determination were not provided, which would have been helpful for reference in other surgical groups.
In 2018, Long et al. published the results of a large RCT that measured safety and short-term efficacy in 425 patients [11]. After randomization, 481 patients were allocated in a 1:1 ratio, with 236 in the VATS group and 245 in the open group. Eight cases of conversion to thoracotomy, including two cases of bleeding and two cases of severe adhesions, were excluded from the study. There were no pneumonectomy patients in the VATS group, while three were in the open group. The pathological results showed that the tumors in the open group were significantly larger, and there was an uneven stage distribution (stage II/III: 25% in VATS and 37% in open). The authors stated that tumor size was not used for randomization, but it is possible that the higher staging in the open group was due to the more thorough lymph node dissection, leading to the discovery of unexpected lymph node metastases, or due to the higher staging of the excluded patients who underwent conversion.
Surgery: open (muscle sparing thoracotomy under the axilla) vs. VATS (not determined but 3-4 holes and utility incision under 5 cm) Limitations: Unequal surgical difficulty and disease severity assignment. Differences in the proportion of high-risk pneumonectomy cases with a higher mortality rate. In

Discussion
There appears to be no significant benefit to using MIS over open (classic) thoracotomy when considering surgical options for lung cancer, except for a shorter hospital stay. According to meta-analysis, we have not found any statistically significant differences in terms of operating time, early mortality, or complications including hemorrhage, prolonged air leakage, respiratory failure, arrhythmia, or postoperative pain between the two approaches. It is important to note that the majority of research on MIS has focused on stage I patients, and tumors included in MIS are generally smaller in size. Therefore, when interpreting the clinical findings and conclusions from these studies, it is crucial not to overstate their significance.
The conclusions of the above-mentioned RCT are as follows [7][8][9][10][11]13,14]. Kirby et al. reported that VATS was not associated with significant benefits [13]. Similarly, Sugi et al. stated that there were no statistical differences between the MIS and the open for overall survival [9]. In the study by Carig et al., they measured perioperative CRP and IL-6, which were lower in VATS, so they concluded that it would be helpful for decreasing recurrence [14]. However, the values had become similar and were almost equal at postoperative hour 200. Moreover, even without considering allocation issues that could disadvantage the open group, the surgery time and mean length of hospital stay were better in the open group. Importantly, it would be difficult to say whether these parameters could influence tumor recurrence and long-term survival because there is no long-term serologic data or biological background. Palade et al. claimed that MIS was as effective as open for mediastinal lymph node dissection (MLND) and that MIS had a better field of vision [10]. However, as pointed out in the discussion at the conference [10], when MLND is performed using VATS instruments, the possibility of overestimation due to fragmentation should be considered. Bendixen et al. concluded that VATS should be the preferred surgical approach for stage I lung cancer because it showed better value for pain and QOL [8]. However, the continuous variable of pain score was dichotomized into moderate to severe (NRS ≥ 3) or not and analyzed as a categorical variable. Moreover, when pain scores were separated into severe (NRS > 7) and non-severe groups, the proportions of patients did not differ between groups during 52 weeks of follow-up (p = 0.17). As the authors noted, they did not obtain complete pain data, and only self-reported QOL was superior in the VATS group. However, most individual dimensions on the EQ5D and EORTC QLQ-C30 questionnaires did not differ significantly between groups at most time points. Moreover, the open group had a shorter surgery time, and all reoperations due to bleeding occurred in the VATS group. Long et al. reported that VATS had an advantage in surgery time and bleeding, but short-term complications did not differ [11]. Despite the allocation issue mentioned earlier, it is important to note that there were no statistically significant differences in chest tube duration, length of hospital stay, or complications between the two groups. Lim et al. concluded that MIS is associated with better recovery of physical function at 5 weeks, but physical function at 6 and 12 months did not differ between the two groups [7]. Although short-term pain scores appeared to be better in MIS, safety issues such as prolonged air leakage and vascular injury were more common in the MIS group, and oncologic outcomes did not differ between the two groups.
According to recent guidelines, MIS is more recommended [28,29], but this may not be appropriate from the following perspectives: First, as previously analyzed, there is insufficient evidence. In addition, in the conclusions of the seven RCTs, three stated that MIS and open are not different [9,10,13], and the remaining four claimed advantages of MIS in limited areas or time points of clinical outcomes, excluding survival [7,8,11,14]. Given the lack of significant benefits for survival, especially in the long term, there is insufficient evidence to prefer a particular approach. Second, it may interfere with surgical decision making. MIS inevitably results in conversion to thoracotomy [32][33][34][35]. Considering that even high-volume centers report significant conversion cases, it is thought to be due to the disease itself and individual physical status rather than a problem with the technique [33,34]. Therefore, when the purpose of surgery is to treat the cancer and improve survival, surgeons can decide on the appropriate timing for conversion based on their experience and judgment. However, in situations where MIS is more recommended by the guidelines, surgeons may obsess over MIS to avoid the non-recommended open approach, which can compromise clinical outcomes due to prolonged surgery time and increased bleeding [32,36]. Third, it can hinder the rapport between surgeons and patients. Patients who experience unavoidable conversion may think that they received surgery that was contrary to the guideline, which can lead medical professionals to feel guilty about not providing the best treatment [37]. This can also have a negative impact on the long-term survival of patients [38,39]. Lastly, recommending MIS can accelerate medical inequality. If two approaches have equal value, individuals will choose cost-effective treatments based on their economic means. However, recommending MIS as the preferred treatment option without considering its limited accessibility in low-income countries and populations [26,[40][41][42][43], as well as the limited evidence for its benefits, could result in unreasonable medical inequalities. Moreover, assuming that MIS is less costly than open surgery, as some studies suggest [40,44], vulnerable groups may be compelled to choose expensive and less-valued treatments (i.e., open surgery).
There is no concrete evidence to suggest whether VATS or open mediastinal lymph node dissection is superior to the other. Most agree that it is useful to thoroughly examine mediastinal lymph nodes [45,46]. However, there is disagreement regarding whether to perform sampling or dissection, and there are concerns regarding MIS, such as whether fragmentation occurs more frequently due to the characteristics of the instruments, whether a sufficient number of lymph nodes can be gathered at various stations according to the guidelines, whether it has an impact on survival rates, or whether it affects up-or downstaging after surgery [10,47]. In related studies, there is the above-mentioned RCT by Palade [47]. First, mediastinal lymph node dissection following international guidance is a minority, and there is no difference in the completeness of mediastinal lymph node dissection between procedures. Second, up-or down-staging after surgery was more common in the open group. Possible reasons for this include selection bias due to retrospective studies and an uneven distribution of stages. However, it should not be overlooked that the open group effectively detected occult lymph node metastases as expected, especially in those with higher T stages. Further studies that are precisely designed are required, as there may be differences in survival rates depending on how mediastinal lymph nodes are managed [45,48].

Conclusions
The choice between MIS and open thoracotomy should be considered value-neutral until decisive evidence emerges from the perspectives of oncologic concern and survival. The decision to choose either method should be left to the judgment of the surgeons who have selected lung cancer surgery as their main focus, and the basis of the decision should prioritize maximum patient safety and survival. Of course, the advancement of lung cancer surgery should be minimally invasive, and in this regard, we are following a proper process. However, such efforts should not undervalue proven surgical methods without sufficient evidence. It is important not to forget that the primary value of lung cancer surgery is to treat the cancer and improve survival rates.
Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/cancers15092630/s1, Figure S1: Forest plot of comparing age in study population according to surgical approach, Figure S2: Forest plot of comparing male proportion in study population according to surgical approach, Figure S3: Forest plot of comparing adenocarcinoma proportion in study population according to surgical approach, Figure S4: Forest plot of comparing tumor size in study population according to surgical approach, Figure S5: Forest plot of comparing proportion of patients with prolonged pain according to surgical approach.